CpG pretreatment enhances antiviral T-cell immunity against cytomegalovirus.

Major histocompatibility complex class I-restricted T-cell immunity is essential to control infection with cytomegalovirus (CMV), a clinically important virus that causes significant disease in immunocompromised individuals. Cross-presentation is considered the primary mode of antigen presentation to generate protective antiviral CD8⁺ T-cell immunity. Herpesviruses, including CMV, encode numerous proteins that interfere with direct antigen presentation, leading to the paradigm that T-cell immunity to these pathogens necessitates cross-presentation. However, the antigen presentation requirements needed to generate a protective T-cell response to CMV remain unknown. Here, we show that a fully functional antiviral CD8⁺ T-cell response can be generated in a system where cross-presentation is shut down by pretreatment with CpG. Notably, in this setting, CD8⁺ T cells demonstrate accelerated control of infection, and organ pathology is limited. These data indicate that protective antiviral T-cell immunity to CMV is generated by direct presentation and can be enhanced by pretreatment with CpG.